EP0387000A2 - Medicament for the treatment of thrombus, inflammation and high blood pressure - Google Patents
Medicament for the treatment of thrombus, inflammation and high blood pressure Download PDFInfo
- Publication number
- EP0387000A2 EP0387000A2 EP90302374A EP90302374A EP0387000A2 EP 0387000 A2 EP0387000 A2 EP 0387000A2 EP 90302374 A EP90302374 A EP 90302374A EP 90302374 A EP90302374 A EP 90302374A EP 0387000 A2 EP0387000 A2 EP 0387000A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- desaturase
- acid
- dioxabicyclo
- octane
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention provides an inhibitor for ⁇ 5-desaturase which specifically inhibits a conversion of dihomo- ⁇ -linolenic acid to arachidonic acid.
- This inhibitor remarkably increases, in vivo, an amount of dihomo- ⁇ -linolenic acid in comparison with arachidonic acid.
- the present invention provides a composition for an inhibition of ⁇ 5-desaturase, comprising a compound selected from the group consisting of lignan compounds, curcumin and piperonyl butoxide.
- the increase of the dihomo- ⁇ -linolenic acid level leads to an increase of the eicosanoid thereof, i.e., prostaglandin G1 (PGG1); prostaglandin H1 (PGH1); prostaglandin D1 (PGD1); prostaglandin E1 (PGE1); prostaglandin F 1 ⁇ (PGF 1 ⁇ ); thromboxane A1 (TXA1); thromboxane B1 (TXB1), 12-(S)-hydroxy-8,10-pentadecadienic acid (HHD); 11-hydroperoxy-8,12,14-eicosatrienoic acid (11-HPETRE); 12-hydroperoxy-8,10,14-eicosatrienoic acid (12-HPETRE); 15-hydroperoxy-8,11,13-eicosatrienoic acid (15-HPETRE); 11-hydroxy-8,12,14-eicosatrienoic acid (11-HETRE); 12-hydroxy-8,10
- Lignan compounds as enzyme inhibitors of the present invention can be prepared, for example, as follows. First, an extract containing the lignans is obtained from sesame oil.
- the sesame oil may be purified sesame oil or crude sesame oil prior to a decoloring step. To obtain the extract, sesame oil is extracted with an organic solvent which is substantially immiscible with the sesame oil and can extract and dissolve effective ingredients.
- the organic solvents are, for example, acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, and the like.
- sesame oil and the solvent are homogeneously mixed, and the mixture is allowed to stand at a low temperature, for example, -80°C. Phases are separated by a conventional procedure such as centrifugation to obtain an organic phase, which is then evaporated to obtain an extract. Next, individual compounds can be isolated from the extract. To this end, the extract can be separated by a conventional procedure, such as column chromatography, high performance liquid chromatography, distillation, crystallization, or a combination thereof. More specifically, the extract is subjected to high performance liquid chromatography using a reverse column (5C18) and an eluate, i.e., methanol/water (60:40) to obtain fractions containing desired lignans. After distilling off the solvent a crystal is obtained which is then recrystallized from ethanol. In this manner, sesamin, episesamin, sesaminol and episesaminol are obtained from purified sesame oil.
- a reverse column 5C18
- an eluate i.
- an extract useful for the present invention can be obtained from sesame seeds.
- sesame seeds if necessary after grinding, are extracted with any solvent able to extract the sesame oil, for example, an organic solvent described above. After separating the solvent from the residue, the solvent is evaporated to obtain an extract.
- the present enzyme inhibitors can be also used in combination with other materials, such as sugars, lipids, proteins or the like, to enhance the effects of the enzyme inhibitors as functional factors. Further, to enhance the effects of the enzyme inhibitors, they may be used in combination with a lipid, for example, a fatty acid having 2 to 20 carbon atoms, such as acetic acid, propionic acid, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo- ⁇ -linolenic acid or the like, alone or in the form of salt such as sodium salt, potassium salt or ammonium salt, ester such as methyl ester or ethyl ester.
- a fatty acid having 2 to 20 carbon atoms such as ace
- oils containing such fatty acids for example, conventional oils such as camellia oil, castor oil, chlorophyll oil, corn oil, cottonseed oil, croton oil, linseed oil, olive oil, peanut oil, rapeseed oil, sesame oil, soybean oil, tung oil, whale oil, and coconut oil can be used.
- conventional oils such as camellia oil, castor oil, chlorophyll oil, corn oil, cottonseed oil, croton oil, linseed oil, olive oil, peanut oil, rapeseed oil, sesame oil, soybean oil, tung oil, whale oil, and coconut oil can be used.
- a 50 mM phosphate buffer pH 7.4 containing 0.15M KCl, 5 mM MgCl2 ⁇ 6H2O, 1 mM EDTA, 0.25M saccharose and 1.5 mM glutathione was used.
- the liver of a Wister male rat was perfused with physiological saline and removed, and to the removed liver was added 4-fold by weight of the homogenization solution, and the whole was homogenized.
- the homogenate was centrifuged at 10,000 xg for 20 minutes to obtain a supernatant, which was centrifuged at 100,000 xg for one hour to obtain a pellet.
- the pellet was suspended in the homogenization solution to obtain a microsome solution containing 12.24 mg/ml protein.
- the above-mentioned procedures were carried out at 4°C.
- the reaction mixture was evaporated in a centrifuge evaporator to remove the solvent, whereby methyl esters of the resulting fatty acids were obtained.
- the esters were separated on a 10% AgNO3 silica gel plate using petroleum ether/ethyl ether (1:1) as a developing solvent.
- Silica gel portions corresponding to the substrate dihomo- ⁇ -linolenic acid and the product arachidonic acid respectively were peeled off, and to 5 ml of toluene-based scintillation fluid solution was added to the silica gel to measure the radioactivity by a scintillation counter.
- the radioactivity of the generated arachidonic acid was determined by subtracting a radioactivity at the onset of the reaction from a radioactivity after the reaction.
- the enzyme inhibitory activities of sesamin, episesamin and sesamomolin were measured according to the above-mentioned procedure, except that the reaction mixture contained 0.001 to 0.5 mg/ml sesamin, episesamin or sesamolin.
- the radioactivity was measured as described above, and the percent inhibition was calculated.
- Fig. 1 The inhibitory action of sesamin on ⁇ 5-desaturase, ⁇ 6-desaturase and ⁇ 9-desaturase is shown in Fig. 1; and the inhibitory action of episesamin and sesamolin on ⁇ 5-desaturase and ⁇ 6-desaturase is shown in Figs. 2 and 3.
- sesamin, episesamin and sesamolin inhibited the ⁇ 5-desaturation reaction from dihomo- ⁇ -linolenic acid to arachidonic acid.
- sesamin, episesamin and sesamolin inhibit ⁇ 5-desaturase occurring in animals, which inhibit the conversion of dihomo- ⁇ -linolenic acid to arachidonic acid.
- other lignan compounds can be used, for example, an extract prepared from sesame oil by organic solvent extraction and a component therein such as sesaminol [2-(3,4-methylenedioxy-6-hydroxyphenyl)-6-(3,4-methylenedioxyphenyl)-cis-dioxabicyclo[3,3,0]octane, episesaminol, as well as an extract from sesame seeds by acetone and a component therein, such as 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane,
- EPO evening primrose oil
- SFO safflower oil
- test groups were designated EPO-0, EPO-10 and EPO-100, as well as SFO-0, SFO-10 and SFO-100, respectively.
- body weight, liver weight, plasma cholesterol, plasma triglyceride, plasma lipid, ⁇ 5-desaturase activity and ⁇ 6-desaturase activity in liver microsome, PGI2 production by the aorta, and an amount of TXA2 in plasma were measured.
- the feeding of sesame oil extract for 3 weeks has no influence on the increase of body weight and liver weight, and therefore, does not influence the growth.
- the ⁇ 5-desaturase activity in microsome was reduced in rats which received the extract.
- the feeding of the extract provided a tendency toward a lowering of cholesterol levels.
- the present composition comprising ⁇ 5-desaturase inhibitor can be used specifically to inhibit ⁇ 5-desaturase occurring in animals, such that an in vivo level of dihomo- ⁇ -linolenic acid increases and prostaglandin 1 series compound is derived from dihomo- ⁇ -linolenic acid and a cascade thereof, resulting in an improvement of inflammation, thrombosis and hypertension conditions.
- the present desaturase inhibitors did not effect PGI2 production by the aorta and an amount of TXA2 in plasma, showing that the present inhibitors do not influence the arachidonic acid cascade.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
- The present invention provides an inhibitor for Δ⁵-desaturase which specifically inhibits a conversion of dihomo-γ-linolenic acid to arachidonic acid. This inhibitor remarkably increases, in vivo, an amount of dihomo-γ-linolenic acid in comparison with arachidonic acid.
- Various studies relating to the actions of essential fatty acids on an organism show that not only there are two metabolic pathways for essential fatty acids, which pathways strongly influence each other, but also in the same metabolic pathway there are various metabolites which act antagonistically, and therefore, to enhance an action it is necessary not only to administer a related metabolite but also to inhibit an antagonistic action against the above-mentioned action. In the case of dihomo-γ-linolenic acid and a metabolite thereof, i.e., arachidonic acid, an eicosanoid derived from dihomo-γ-linolenic acid and an eicosanoid derived from arachidonic acid antagonistically influence each other, and therefore, to enhance the effects of an administration of dihomo-γ-linolenic acid, it is necessary to inhibit a conversion of dihomo-γ-linolenic acid to arachidonic acid. At present, although a series of
prostaglandin 1 derived from dihomo-γ-linolenic acid is known to have an antithrombus activity, unless inhibiting the conversion of dihomo-γ-linolenic acid to arachidonic, the desired expected effect provided by administering dihomo-γ-linolenic acid is not obtained. - It is known that among lignan compounds, sesaminol, episesaminol, 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7- dioxabicyclo[3.3.0]octane and 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane are comparable with or superior to sesaminol and γ-tocopherol in the antioxidation activity thereof, and are being developed as antioxidants. Moreover, these lignan compounds are under study for possible application for an inhibition of lipid peroxidation in vivo which is considered a cause of senility, oncogenesis and the like. However, among lignan compounds, an anti-oxidation activity of sesamin, episesamin and sesamolin is not known.
- Moreover, it is not known that the above-mentioned lignan compounds inhibit Δ⁵-desaturase, which catalyzes the conversion of dihomo-γ-linolenic acid to arachidonic acid.
- In addition, it is not known that curcumin and piperonyl inhibit Δ⁵- desaturase.
- Accordingly, the present invention provides a composition for an inhibition of Δ⁵-desaturase, comprising a compound selected from the group consisting of lignan compounds, curcumin and piperonyl butoxide.
- In another aspect, these compounds are provided for the medical use.
- Fig. 1 is a graph showing that sesamin specifically inhibits Δ⁵-desaturase;
- Fig. 2 is a graph showing that episesamin specifically inhibits Δ⁵-desaturase; and
- Fig. 3 is a graph showing that sesamolin specifically inhibits Δ⁵-desaturase.
- The present inventors found that lignan compounds, which inhibit Δ⁵-desaturase in a biosynthesis pathway for highly unsaturated fatty acids in arachidonic acid-producing microorganisms, also inhibit Δ⁵-desaturase in an enzyme cascade in rat liver microsome.
- This inhibitory activity is provided by lignans such as sesamin, sesaminol, episesamin, episesaminol, sesamolin, 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane and 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane; curcumin of plant origin; as well as piperonyl butoxide which is a synergistic agent for agricultural chemicals.
- The inhibition of the Δ⁵-desaturase increases a level of dihomo-γ-linolenic acid in vivo, which in turn increases levels of
prostaglandin 1 series compounds through the enhancement of dihomo-γ-linolenic acid cascade. Namely, the increase of the dihomo-γ-linolenic acid level leads to an increase of the eicosanoid thereof, i.e., prostaglandin G₁ (PGG₁); prostaglandin H₁ (PGH₁); prostaglandin D₁ (PGD₁); prostaglandin E₁ (PGE₁); prostaglandin F1α (PGF1α ); thromboxane A₁ (TXA₁); thromboxane B₁ (TXB₁), 12-(S)-hydroxy-8,10-pentadecadienic acid (HHD); 11-hydroperoxy-8,12,14-eicosatrienoic acid (11-HPETRE); 12-hydroperoxy-8,10,14-eicosatrienoic acid (12-HPETRE); 15-hydroperoxy-8,11,13-eicosatrienoic acid (15-HPETRE); 11-hydroxy-8,12,14-eicosatrienoic acid (11-HETRE); 12-hydroxy-8,10,14-eicosatrienoic acid (12-HETRE); 15-hydroxy-8,11,13-eicosatrienoic acid (15-HETRE); 8-hydroperoxy-9,11,14-eicosatrienoic acid (8-HPETRE); 8-hydroxy-9,11,14-eicosatrienoic acid (8-HETRE); 8,9-leukotriene A₃ (8,9-LTA₃); 8,15-leukotriene B₃ (8,15-LTB₃); 8,9-leukotriene C₃ (8,9-LTC₃); 8,9-leukotriene D₃ (8,9-LTD₃); 8,9-leukotiene E₃ (8,9-LTE₃); 8,9-leukotriene F₃ (8,9-LTF₃), and the like. - These derived compounds provide advantageous activities. For example, it is known that PGE₁ exhibits anti-platelet aggregation activity, vasodilatation activity, bronchodilatation activity, and antiinflammation activity, and are being studied for clinical application to treatment of pulmonary trunk thrombosis, thromboembolism, pulmonary hypertension, blonchial asthma, congestive heart, new born blue disease, and skin diseases. Moreover, the compounds overcomes the disadvantages that PGE₁, which having very strong biological activities, can be only partially absorbed as an active form in an oral administration of native prostaglandin (PG). This drawback is caused by an inactivation of PG at the wall of gastro-intestinal tract, and therefore, it has been considered that the development of a stable PG derivative or an injection of PG is necessary. Nevertheless, use of inhibitor for Δ⁵-desaturase may regulate a fatty acid biosynthesis in vivo, and provides various pharmacological activities, such as anti-inflammation activity, anti-thrombus activity, blood pressure-lowering activity and the like through increasing levels of dihomo-γ-linolenic acid and eicosanoids thereof.
- Moreover, the above-mentioned active compounds are promising as functional factors for functional foods. Since the lignan compounds having an activity of inhibiting Δ⁵-desaturase are those inherently contained in edible oils, then are safe as functional factors for functional foods.
- Lignan compounds as enzyme inhibitors of the present invention can be prepared, for example, as follows. First, an extract containing the lignans is obtained from sesame oil. The sesame oil may be purified sesame oil or crude sesame oil prior to a decoloring step. To obtain the extract, sesame oil is extracted with an organic solvent which is substantially immiscible with the sesame oil and can extract and dissolve effective ingredients. The organic solvents are, for example, acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, and the like. To extract the effective ingredients, for example, sesame oil and the solvent are homogeneously mixed, and the mixture is allowed to stand at a low temperature, for example, -80°C. Phases are separated by a conventional procedure such as centrifugation to obtain an organic phase, which is then evaporated to obtain an extract. Next, individual compounds can be isolated from the extract. To this end, the extract can be separated by a conventional procedure, such as column chromatography, high performance liquid chromatography, distillation, crystallization, or a combination thereof. More specifically, the extract is subjected to high performance liquid chromatography using a reverse column (5C₁₈) and an eluate, i.e., methanol/water (60:40) to obtain fractions containing desired lignans. After distilling off the solvent a crystal is obtained which is then recrystallized from ethanol. In this manner, sesamin, episesamin, sesaminol and episesaminol are obtained from purified sesame oil.
- Alternatively, an extract useful for the present invention can be obtained from sesame seeds. In this case, sesame seeds, if necessary after grinding, are extracted with any solvent able to extract the sesame oil, for example, an organic solvent described above. After separating the solvent from the residue, the solvent is evaporated to obtain an extract. An extract obtained from crude sesame oil, or sesame seeds contains lignans such as sesamin, sesaminol, episesamin, episesaminol, sesamolin, 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane and 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane. These lignans can be isolated as described above.
- Note, the above-mentioned processes for the isolation of lignans are examples only, and this can be obtained with other processes.
- Moreover, the present enzyme inhibitors can be used as a form of derivative of glycoside or the like, so far as the enzyme inhibitory activity is maintained.
- The Δ⁵-desaturase inhibitor can be used to increase an in vivo level of dihomo-γ-linolenic acid, and to enhance the dihomo-γ-linolenic acid cascade, resulting in an increase of the levels of
prostaglandin 1 series compounds. On the basis of these properties, the present enzyme inhibitors are promising as medicaments for anti-inflammation, antithrombus, blood pressure lowering activities and the like. - The lignan compounds, piperonyl butoxide, or curcumin used as active ingredient in the present enzyme inhibitory composition can be used alone, or in an appropriate combination. These compounds are dissolved in ethanol, and the resulting solution diluted with water before use. Alternatively, the compounds may be formulated as an emulsion in an aqueous solution, or in capsules. Moreover, the present active ingredient can be converted to inclusion bodies with cyclodextrin, which are then formulated to powders, particles, tablets, and other conventional formulations.
- The present enzyme inhibitors can be also used in combination with other materials, such as sugars, lipids, proteins or the like, to enhance the effects of the enzyme inhibitors as functional factors. Further, to enhance the effects of the enzyme inhibitors, they may be used in combination with a lipid, for example, a fatty acid having 2 to 20 carbon atoms, such as acetic acid, propionic acid, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo-γ-linolenic acid or the like, alone or in the form of salt such as sodium salt, potassium salt or ammonium salt, ester such as methyl ester or ethyl ester. Moreover, oils containing such fatty acids, for example, conventional oils such as camellia oil, castor oil, chlorophyll oil, corn oil, cottonseed oil, croton oil, linseed oil, olive oil, peanut oil, rapeseed oil, sesame oil, soybean oil, tung oil, whale oil, and coconut oil can be used.
- The present invention will now be further illustrated by, but is no means limited to, the following examples.
- As a homogenization solution, a 50 mM phosphate buffer (pH 7.4) containing 0.15M KCl, 5 mM MgCl₂·6H₂O, 1 mM EDTA, 0.25M saccharose and 1.5 mM glutathione was used. The liver of a Wister male rat was perfused with physiological saline and removed, and to the removed liver was added 4-fold by weight of the homogenization solution, and the whole was homogenized. The homogenate was centrifuged at 10,000 xg for 20 minutes to obtain a supernatant, which was centrifuged at 100,000 xg for one hour to obtain a pellet. The pellet was suspended in the homogenization solution to obtain a microsome solution containing 12.24 mg/ml protein. The above-mentioned procedures were carried out at 4°C.
- To assay the Δ⁵-desaturase activity, 100 µl of the rat liver microsome solution was added to 1 ml of 0.1M phosphate buffer (PH7.4) containing 0.25M saccharose, 0.15M KCl, 1.5 mM glutathione, 45 mM NaF, 0.5 mM nicotinamide, 5 mM MgCl₂·6H₂O, 7.5 mM ATP, 0.4 mM COA·Na₂ , 1.5 mM NADH, and 100 µM dihomo-γ-linolenic acid containing 0.1 µCi (1.7 nmoles) [2-¹⁴C]-dihomo-γ-linolenic acid per 1 ml, the mixture was incubated at 37°C for one hour, followed by an addition of 5 ml of ethanol to terminate the reaction. To the reaction mixture was added 1 ml of 4N KOH, and mixture was incubated at 60°C for 30 minutes for saponification. After the reaction, 3 ml of water, 100 µg of dihomo-γ-linolenic acid and 1 ml of 6N HCl were added thereon, and fatty acids in the reaction mixture were extracted twice with 5 ml of hexane. The extract was evaporated in a centrifuge evaporator and 1 ml of ethyl ether/methanol (9:1) was added to the residue, and the fatty acids were methylated with diazomethane. After allowing to stand at a room temperature for 30 minutes, the reaction mixture was evaporated in a centrifuge evaporator to remove the solvent, whereby methyl esters of the resulting fatty acids were obtained. The esters were separated on a 10% AgNO₃ silica gel plate using petroleum ether/ethyl ether (1:1) as a developing solvent. Silica gel portions corresponding to the substrate dihomo-γ-linolenic acid and the product arachidonic acid respectively were peeled off, and to 5 ml of toluene-based scintillation fluid solution was added to the silica gel to measure the radioactivity by a scintillation counter. The radioactivity of the generated arachidonic acid was determined by subtracting a radioactivity at the onset of the reaction from a radioactivity after the reaction.
- The enzyme inhibitory activities of sesamin, episesamin and sesamomolin were measured according to the above-mentioned procedure, except that the reaction mixture contained 0.001 to 0.5 mg/ml sesamin, episesamin or sesamolin. The radioactivity was measured as described above, and the percent inhibition was calculated.
- For the assay of Δ⁶-desaturase and Δ⁹-desaturase, substantially the same procedure as described above was repeated, except that 100 nmoles of linoleic acid including 0.1 µCi (1.70 nmoles) of [1-¹⁴C]-linoleic acid, and 100 nmoles of stearic acid including 0.1 µCi (1.79 nmoles) of [1-¹⁴C]-stearic acid were used as substrates respectively; and petroleum ether/ethyl ether (7:3) and petroleum ether/ethyl ether (95:5) were used respectively to separate the substrate and product in the thin layer chromatography step. The inhibitory action of sesamin, episesamin and sesamolin on Δ⁶- desaturase and Δ⁹-desaturase was measured as above.
- The inhibitory action of sesamin on Δ⁵-desaturase, Δ⁶-desaturase and Δ⁹-desaturase is shown in Fig. 1; and the inhibitory action of episesamin and sesamolin on Δ⁵-desaturase and Δ⁶-desaturase is shown in Figs. 2 and 3. As seen from Figs. 1, 2 and 3, sesamin, episesamin and sesamolin inhibited the Δ⁵-desaturation reaction from dihomo-γ-linolenic acid to arachidonic acid.
- From this result, it is clear that sesamin, episesamin and sesamolin inhibit Δ⁵-desaturase occurring in animals, which inhibit the conversion of dihomo-γ-linolenic acid to arachidonic acid. Moreover, in addition to sesamin, episesamin and sesamolin, it is believed that other lignan compounds can be used, for example, an extract prepared from sesame oil by organic solvent extraction and a component therein such as sesaminol [2-(3,4-methylenedioxy-6-hydroxyphenyl)-6-(3,4-methylenedioxyphenyl)-cis-dioxabicyclo[3,3,0]octane, episesaminol, as well as an extract from sesame seeds by acetone and a component therein, such as 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane and 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3,3,0]octane specifically inhibit Δ⁵-desaturase in vivo (see Japanese Patent Application No. 63-53642; Japanese Unexamined Patent Publication KOKAI No. H1-243992).
- According to the same procedure as described in Example 1, sesamin, curcumin (Wako Pure Chemical Industries, Japan) or piperonyl butoxide (Ardrich) was added in a reaction mixture at a concentration of 0.03 mg/ml. The result is shown in Table. 1.
Table 1 Test compound Inhibition on Δ⁵-desaturase Inhibition on Δ⁶- (%) (%) Sesamin 39.23 0 Curcumin 50.56 36.13 Piperonyl butoxide 32.47 0 - First, 20 g of sesame oil was dissolved in 150 ml of acetone, and the solution was allowed to stand at -80°C overnight to precipitate an oil fraction. After filtration, the filtrate was evaporated in a rotary evaporator to remove the solvent, and an extract containing lignan compounds such as sesamin, which are Δ⁵-desaturase inhibitors, was obtained.
- SD male rats 4 weeks old (102 g) were fed for 3 weeks. The feed contained 10% evening primrose oil (EPO) or safflower oil (SFO) as a fat source, and the above-prepared extract in an amount corresponding to 0 g, 10 g or 100 g of sesame oil (test groups were designated EPO-0, EPO-10 and EPO-100, as well as SFO-0, SFO-10 and SFO-100, respectively). After 3 weeks, the body weight, liver weight, plasma cholesterol, plasma triglyceride, plasma lipid, Δ⁵-desaturase activity and Δ⁶-desaturase activity in liver microsome, PGI₂ production by the aorta, and an amount of TXA₂ in plasma were measured. The desaturase activity was measured as described in Example 1, and other measurements were carried out according to conventional procedures. The results are shown in Tables 2 and 3.
Table 2 No. Initial body weight Final body weight Increase Increase/day Tatal feeding taken Feeding taken/day (g) (g) (g) (g/day) (g) (g/day) EPO-0 102 ± 3 270 ± 11 167 ± 10 8 ± 0 384 ± 16 18 ± 1 EPO-10 103 ± 3 265 ± 13 162 ± 11 8 ± 1 382 ± 13 18 ± 1 EPO-100 103 ± 2 265 ± 10 161 ± 8 8 ± 0 385 ± 13 18 ± 1 SFO-0 103 ± 2 269 ± 7 166 ± 6 8 ± 0 385 ± 8 18 ± 0 SFO-10 103 ± 2 276 ± 7 173 ± 6 8 ± 0 402 ± 14 19 ± 1 SFO-100 103 ± 2 269 ± 7 166 ± 5 8 ± 0 388 ± 9 18 ± 1 No. Efficiency of feeding Liver weight Plasma CHOL Plasma TG Plasma PL (g) (mg/dl) (mg/dl) (mg/dl) EPO-0 0.43 ± 0.01 14.57 ± 0.01 109.4 ± 5.7 189.7 ± 15.8 251.8 ± 16.7 EPO-10 0.42 ± 0.02 14.59 ± 0.83 101.9 ± 6.8 165.2 ± 11.6 239.0 ± 17.5 EPO-100 0.42 ± 0.01 16.71 ± 0.94 75.1 ± 4.4 149.9 ± 24.9 216.3 ± 8.2 SFO-0 0.43 ± 0.01 14.49 ± 0.61 89.4 ± 2.6 253.9 ± 29.2 267.7 ± 9.4 SFO-10 0.43 ± 0.01 14.60 ± 0.78 83.4 ± 4.5 175.0 ± 18.9 238.3 ± 10.6 SFO-100 0.43 ± 0.01 16.83 ± 0.72 74.8 ± 4.7 163.6 ± 14.1 222.3 ± 11.7 CHOL: cholesterol TG: triglyceride PL: phospholipid Table 3 Δ⁵- and Δ⁶-desaturase activity in rat liver microsome (pmol/min/mg protein) EPO SFO 0 10 100 0 10 100 Δ⁶-desaturase activity 42.1 35.0 59.4↑ 34.1 34.2 61.7↑ Δ⁵-desaturase activity 48.6 39.5 34.8↓ 55.5 48.8 25.2↓ - As seen from the above, the feeding of sesame oil extract for 3 weeks has no influence on the increase of body weight and liver weight, and therefore, does not influence the growth. Moreover, the Δ⁵-desaturase activity in microsome was reduced in rats which received the extract. Also, the feeding of the extract provided a tendency toward a lowering of cholesterol levels.
- As described above, the present composition comprising Δ⁵-desaturase inhibitor can be used specifically to inhibit Δ⁵-desaturase occurring in animals, such that an in vivo level of dihomo-γ-linolenic acid increases and
prostaglandin 1 series compound is derived from dihomo-γ-linolenic acid and a cascade thereof, resulting in an improvement of inflammation, thrombosis and hypertension conditions. Moreover, the present desaturase inhibitors did not effect PGI₂ production by the aorta and an amount of TXA₂ in plasma, showing that the present inhibitors do not influence the arachidonic acid cascade.
Claims (7)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5295089 | 1989-03-07 | ||
JP52950/89 | 1989-03-07 | ||
JP2020469A JP3070611B2 (en) | 1989-03-07 | 1990-02-01 | △ ▲ Top 5 ▼ ―Unsaturated enzyme inhibitor |
JP20469/90 | 1990-02-01 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0387000A2 true EP0387000A2 (en) | 1990-09-12 |
EP0387000A3 EP0387000A3 (en) | 1991-08-07 |
EP0387000B1 EP0387000B1 (en) | 1995-05-24 |
Family
ID=26357435
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90302374A Expired - Lifetime EP0387000B1 (en) | 1989-03-07 | 1990-03-06 | Medicament for the treatment of thrombus, inflammation and high blood pressure |
Country Status (6)
Country | Link |
---|---|
US (1) | US5336496A (en) |
EP (1) | EP0387000B1 (en) |
JP (1) | JP3070611B2 (en) |
AT (1) | ATE122884T1 (en) |
DE (1) | DE69019565T2 (en) |
ES (1) | ES2072387T3 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995022971A1 (en) * | 1994-02-25 | 1995-08-31 | New England Deaconess Hospital Corporation | Anti-inflammatory and infection protective effects of sesamin-based lignans |
WO1995028163A1 (en) * | 1994-04-15 | 1995-10-26 | New England Deaconess Hospital Corporation | Enteral formulations for the treatment of inflammation and infection containing a saponin, possibly in combination with other compounds |
EP0681788A2 (en) * | 1994-05-12 | 1995-11-15 | Suntory Limited | Dioxabicyclo[3.3.0] octane derivatives, e.g. sesamin etc., for prevention or alleviation of allergy symptoms |
EP0729753A1 (en) * | 1995-02-01 | 1996-09-04 | Suntory Limited | Agents for treatment or prevention of hypertension and related symptons and disorders; their preparation and use |
US5637610A (en) * | 1991-06-15 | 1997-06-10 | Suntory Limited | Composition containing dioxabicyclo [3.3.0] octane derivative |
EP0782827A1 (en) * | 1995-07-04 | 1997-07-09 | Suntory Limited | FOOD COMPOSITION CONTAINING BALANCING AGENT FOR $g(v)-6 AND $g(v)-3 UNSATURATED FATTY ACIDS |
EP0818196A1 (en) * | 1989-07-21 | 1998-01-14 | Suntory Limited | Food or drink containing dioxabicyclo (3.3.0) octane compounds |
EP1264596A2 (en) * | 2001-06-05 | 2002-12-11 | Kao Corporation | Use of a ferulic acid derivative as a preventive or remedy for hypertension |
WO2004020474A1 (en) * | 2002-08-29 | 2004-03-11 | Hormos Medical Corporation | Lignan complexes |
US7943663B2 (en) | 2005-09-30 | 2011-05-17 | Suntory Holdings Limited | Process and an apparatus for producing episesamin-rich compositions |
US9408803B2 (en) | 2006-03-31 | 2016-08-09 | Suntory Holdings Limited | Compositions containing lignan-class compounds |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06227977A (en) * | 1993-02-01 | 1994-08-16 | Suntory Ltd | Active oxygen eliminating agent |
US5606035A (en) * | 1994-01-25 | 1997-02-25 | Kawakishi; Shunrou | Sesaminol glucosides |
US5811313A (en) * | 1997-06-17 | 1998-09-22 | King Pharmaceuticals, Inc. | Identification test for highly refined sesame oil |
US7138431B1 (en) | 1998-02-23 | 2006-11-21 | Wake Forest University | Dietary control of arachidonic acid metabolism |
US6107334A (en) * | 1998-02-23 | 2000-08-22 | Wake Forest University | Dietary control of arachidonic acid metabolism |
JPH11246427A (en) * | 1998-03-04 | 1999-09-14 | Kadoya Sesami Mills Inc | Agent for activating metabolism of saccharide and lipid |
EP2172560A3 (en) * | 2000-02-24 | 2010-09-29 | Xenon Pharmaceuticals Inc. | stearoyl-coa desaturase to identify triglyceride reducing therapeutic agents |
US20030064950A1 (en) * | 2001-02-23 | 2003-04-03 | Ntambi James M. | Methods for reducing body fat and increasing lean body mass by reducing stearoyl-CoA desaturase 1 activity |
ATE402262T1 (en) * | 2000-09-26 | 2008-08-15 | Xenon Pharmaceuticals Inc | METHODS AND COMPOSITIONS USING A STEAROYL-COA DESUTURASE-HSCD5 |
WO2002040666A2 (en) * | 2000-11-17 | 2002-05-23 | Xenon Genetics Inc. | Fat regulated genes, uses thereof, and compounds for modulating same |
JP2005500857A (en) * | 2001-08-29 | 2005-01-13 | ゼノン ジェネティクス,インコーポレイテッド | High-throughput screening analysis using fatty acid synthase |
JP4388248B2 (en) * | 2001-10-29 | 2009-12-24 | 株式会社日立製作所 | Optimal portfolio determination method and apparatus |
JP5384777B2 (en) * | 2001-12-18 | 2014-01-08 | 有限会社大長企画 | Strong muscle agent, anti-inflammatory agent |
US7867479B2 (en) * | 2003-11-14 | 2011-01-11 | Bug Buster, Ltd. | Compounds to affect insect behavior and/or bird behavior |
US6958146B2 (en) * | 2003-05-28 | 2005-10-25 | Bug Buster Ltd. | Compounds to affect insect behavior and to enhance insecticides |
KR101327649B1 (en) * | 2005-03-31 | 2013-11-12 | 산토리 홀딩스 가부시키가이샤 | Lignane compound-containing oil-in-water emulsion and composition comprising the same |
JP4876637B2 (en) * | 2006-03-08 | 2012-02-15 | パナソニック株式会社 | Dehumidifier |
WO2008089310A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of obesity |
WO2008089307A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer |
DE112008000860B4 (en) | 2007-03-30 | 2016-07-28 | Council Of Scientific And Industrial Research | Process for the extraction of bioactive lignans from sesame oil with high yield and purity |
EP2152093A4 (en) * | 2007-05-04 | 2011-05-25 | Jana Pickova | Compound feed for aquaculture |
EP2189160A4 (en) | 2007-09-19 | 2010-10-13 | Suntory Holdings Ltd | Composition comprising sesamin component and vitamin b1 component |
CN105814209B (en) * | 2013-12-04 | 2022-02-25 | 日本水产株式会社 | Microbial oils containing dihomo-gamma-linolenic acid and microbial biomass containing dihomo-gamma-linolenic acid |
KR101641002B1 (en) * | 2014-12-31 | 2016-07-19 | 박상은 | Snow tires with iron pins |
US10639313B2 (en) | 2017-09-01 | 2020-05-05 | Ndsu Research Foundation | Compound for inhibition of delta-5-desaturase (D5D) and treatment of cancer and inflammation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2722911A1 (en) * | 1976-05-20 | 1977-12-01 | Wisconsin Alumni Res Found | GLYCOSIDES OF 2,6-BIS-(HYDROXYPHENYL)-3,7-DIOXABICYCLO SQUARE BRACKETS ON 3.3.0 SQUARE BRACKETS TO OCTANE, PROCESS FOR THEIR PREPARATION AND MEDICINES CONTAINING THEM |
US4427694A (en) * | 1982-06-11 | 1984-01-24 | The Vinoxen Company, Inc. | Sesamin as a psychotropic agent |
FR2574089A1 (en) * | 1984-12-03 | 1986-06-06 | Inst Nat Sante Rech Med | PROCESS FOR THE PRODUCTION OF FATTY ACIDS, PARTICULARLY G-LINOLEIC ACID FROM TETRAHYMENA, PRODUCTS OBTAINED AND MEDICAMENTARY OR FOOD PREPARATION CONTAINING G-LINOLENIC ACID OR DERIVATIVES AS PLAQUETTA ANTI-AGGREGATION AGENT |
EP0255287A2 (en) * | 1986-07-24 | 1988-02-03 | Wakunaga Seiyaku Kabushiki Kaisha | Cerebral-circulation-metabolism-function-improving agent |
EP0322227A2 (en) * | 1987-12-21 | 1989-06-28 | Suntory Limited | Process for production of bishomo-gamma-linolenic acid |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US113713A (en) * | 1871-04-11 | Improvement in medical compounds or bitters | ||
US1518365A (en) * | 1923-06-23 | 1924-12-09 | Shahapzian Nazik | Ointment |
US4044118A (en) * | 1974-05-16 | 1977-08-23 | Texaco Inc. | Solubilizing process for oil insoluble pesticides |
US4083970A (en) * | 1976-12-10 | 1978-04-11 | Stauffer Chemical Company | Activated insecticide composition employing a certain phosphorodithioate and an activator |
GB8729153D0 (en) * | 1987-12-14 | 1988-01-27 | Efamol Ltd | Fatty acid compositions |
US5093249A (en) * | 1989-05-24 | 1992-03-03 | Idemitsu Petrochemical Co., Ltd. | Process for production of dihomo-γ-linolenic acid and inhibitor for unsaturation reaction at Δ5-position of fatty acid |
-
1990
- 1990-02-01 JP JP2020469A patent/JP3070611B2/en not_active Expired - Lifetime
- 1990-03-06 EP EP90302374A patent/EP0387000B1/en not_active Expired - Lifetime
- 1990-03-06 DE DE69019565T patent/DE69019565T2/en not_active Expired - Lifetime
- 1990-03-06 ES ES90302374T patent/ES2072387T3/en not_active Expired - Lifetime
- 1990-03-06 AT AT90302374T patent/ATE122884T1/en active
-
1992
- 1992-04-14 US US07/867,086 patent/US5336496A/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2722911A1 (en) * | 1976-05-20 | 1977-12-01 | Wisconsin Alumni Res Found | GLYCOSIDES OF 2,6-BIS-(HYDROXYPHENYL)-3,7-DIOXABICYCLO SQUARE BRACKETS ON 3.3.0 SQUARE BRACKETS TO OCTANE, PROCESS FOR THEIR PREPARATION AND MEDICINES CONTAINING THEM |
US4427694A (en) * | 1982-06-11 | 1984-01-24 | The Vinoxen Company, Inc. | Sesamin as a psychotropic agent |
FR2574089A1 (en) * | 1984-12-03 | 1986-06-06 | Inst Nat Sante Rech Med | PROCESS FOR THE PRODUCTION OF FATTY ACIDS, PARTICULARLY G-LINOLEIC ACID FROM TETRAHYMENA, PRODUCTS OBTAINED AND MEDICAMENTARY OR FOOD PREPARATION CONTAINING G-LINOLENIC ACID OR DERIVATIVES AS PLAQUETTA ANTI-AGGREGATION AGENT |
EP0255287A2 (en) * | 1986-07-24 | 1988-02-03 | Wakunaga Seiyaku Kabushiki Kaisha | Cerebral-circulation-metabolism-function-improving agent |
EP0322227A2 (en) * | 1987-12-21 | 1989-06-28 | Suntory Limited | Process for production of bishomo-gamma-linolenic acid |
Non-Patent Citations (2)
Title |
---|
BIOLOGICAL ABSTRACT Nb: 76059455 MUKHOPADHYAY A. et al: " Anti-inflammatory and irritant activities of curcumin analogs in rats" & Agents Actions, 12(4)1982,508-515 * |
MEDLINE ABSTRACT Nb: 85140218 LUINI A.G. et al: " Inhibitors of the cytochrome P-450 enzymes block the secretagogue-induced release of corticotropin in mouse pituitary tumor & PROC.NATL.ACAD.SCI.USA, 82(4) 1985, p 1012-41. * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0818196A1 (en) * | 1989-07-21 | 1998-01-14 | Suntory Limited | Food or drink containing dioxabicyclo (3.3.0) octane compounds |
EP0826369A1 (en) * | 1989-07-21 | 1998-03-04 | Suntory Limited | Therapeutic use of dioxabicyclo (3.3.0)octane compounds |
US5637610A (en) * | 1991-06-15 | 1997-06-10 | Suntory Limited | Composition containing dioxabicyclo [3.3.0] octane derivative |
WO1995022971A1 (en) * | 1994-02-25 | 1995-08-31 | New England Deaconess Hospital Corporation | Anti-inflammatory and infection protective effects of sesamin-based lignans |
US5674853A (en) * | 1994-02-25 | 1997-10-07 | Beth Israel Deaconess Medical Center, Inc. | Enternal formulations for treatment of inflammation and infection |
US5762935A (en) * | 1994-02-25 | 1998-06-09 | Beth Israel Deaconess Medical Center, Inc. | Anti-inflammatory and infection protective effects of sesamin-based lignans |
WO1995028163A1 (en) * | 1994-04-15 | 1995-10-26 | New England Deaconess Hospital Corporation | Enteral formulations for the treatment of inflammation and infection containing a saponin, possibly in combination with other compounds |
AU703327B2 (en) * | 1994-05-12 | 1999-03-25 | Suntory Holdings Limited | Agent for prevention or alleviation of allergy sypmtoms |
EP0681788A2 (en) * | 1994-05-12 | 1995-11-15 | Suntory Limited | Dioxabicyclo[3.3.0] octane derivatives, e.g. sesamin etc., for prevention or alleviation of allergy symptoms |
EP0681788A3 (en) * | 1994-05-12 | 1998-01-14 | Suntory Limited | Dioxabicyclo[3.3.0] octane derivatives, e.g. sesamin etc., for prevention or alleviation of allergy symptoms |
EP0729753A1 (en) * | 1995-02-01 | 1996-09-04 | Suntory Limited | Agents for treatment or prevention of hypertension and related symptons and disorders; their preparation and use |
US5889046A (en) * | 1995-02-01 | 1999-03-30 | Suntory Limited | Method for preventing or alleviating cerebral apoplexy |
EP0782827A4 (en) * | 1995-07-04 | 1997-08-20 | ||
EP0782827A1 (en) * | 1995-07-04 | 1997-07-09 | Suntory Limited | FOOD COMPOSITION CONTAINING BALANCING AGENT FOR $g(v)-6 AND $g(v)-3 UNSATURATED FATTY ACIDS |
US5948451A (en) * | 1995-07-04 | 1999-09-07 | Suntory Limited | Method of modifying the balance of omega unsaturated fatty acids using a dioxabicyclo octane derivative |
US6159507A (en) * | 1995-07-04 | 2000-12-12 | Suntory Limited | Food composition containing an omega-6/omega-3 unsaturated fatty acid balance modifier |
EP1264596A2 (en) * | 2001-06-05 | 2002-12-11 | Kao Corporation | Use of a ferulic acid derivative as a preventive or remedy for hypertension |
EP1264596A3 (en) * | 2001-06-05 | 2003-01-08 | Kao Corporation | Use of a ferulic acid derivative as a preventive or remedy for hypertension |
US6894077B2 (en) | 2001-06-05 | 2005-05-17 | Kao Corporation | Preventive or remedy for hypertension |
US7534815B2 (en) | 2001-06-05 | 2009-05-19 | Kao Corporation | Preventive or remedy for hypertension |
US7939563B2 (en) | 2001-06-05 | 2011-05-10 | Kao Corporation | Remedy for hypertension |
WO2004020474A1 (en) * | 2002-08-29 | 2004-03-11 | Hormos Medical Corporation | Lignan complexes |
US7943663B2 (en) | 2005-09-30 | 2011-05-17 | Suntory Holdings Limited | Process and an apparatus for producing episesamin-rich compositions |
US9408803B2 (en) | 2006-03-31 | 2016-08-09 | Suntory Holdings Limited | Compositions containing lignan-class compounds |
Also Published As
Publication number | Publication date |
---|---|
DE69019565D1 (en) | 1995-06-29 |
EP0387000A3 (en) | 1991-08-07 |
DE69019565T2 (en) | 1995-09-28 |
ATE122884T1 (en) | 1995-06-15 |
JPH0327319A (en) | 1991-02-05 |
JP3070611B2 (en) | 2000-07-31 |
US5336496A (en) | 1994-08-09 |
EP0387000B1 (en) | 1995-05-24 |
ES2072387T3 (en) | 1995-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0387000B1 (en) | Medicament for the treatment of thrombus, inflammation and high blood pressure | |
US11285125B2 (en) | Oxidative retinal diseases | |
US11406602B2 (en) | Substances for reducing occurrence of major cardiac events comprising red yeast rice extract and omega-3 polyunsaturated fatty acid or derivative thereof | |
DE60124256T3 (en) | ASPIRIN-RELATED LIPID MEDIATORS | |
JP3065710B2 (en) | Anti-inflammatory agent | |
US7666447B2 (en) | Compositions including Krill extracts and conjugated linoleic acid and methods of using same | |
US5654290A (en) | Polyunsaturated fatty acid based drugs | |
EP3116313B1 (en) | Optic neuropathy treatment and reduction of steroid-induced oxidative stress with stabilized polyunsaturated substances | |
US6136985A (en) | CLA esters and uses thereof | |
EP0488513B1 (en) | Use of dioxabicyclo [3.3.0]octane derivatives for the manufacture of a medicament for inhibiting the metabolism of cholesterol. | |
AU2010237612A1 (en) | Compounds affecting glycemic index | |
JPH0779661B2 (en) | Food composition | |
US20120201912A1 (en) | Substances for reducing occurrence of major cardiac events comprising omega-3 polyunsaturated fatty acid or derivatives thereof and high-monacolin k content red yeast rice extract | |
US20130303602A1 (en) | Novel pterocarpan compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of metabolic disease or complication thereof, or for antioxidant containing the same as an active ingredient | |
KR100964906B1 (en) | Pharmaceutical composition for treating or preventing an inflammatory disease comprising licarin E | |
EP0201159B1 (en) | Pharmaceutical and dietary compositions containing linolenic acids for the treatment of benign prostatic hypertrophy | |
EP0409559B1 (en) | Pharmaceutical uses of fatty acids | |
KR101110742B1 (en) | Composition for preventing or treating metabolic disease comprising ergosterol peroxide, ganodermanondiol or ganoderma mushroom extract | |
EP0202661A2 (en) | Isolation of castanospermine and its use as an antidiabetic agent | |
US6136820A (en) | Isolation of castanospermine and its use as an antidiabetic agent | |
Shchepinov et al. | Oxidative retinal diseases | |
JP3075360B2 (en) | Cholesterol lowering drugs | |
JPH0253726A (en) | Agent for lowering cholesterol and novel phospholipid | |
WO2013138407A1 (en) | Substances for reducing occurrence of major cardiac events comprising epa or derivatives thereof, optionally, dha or derivatives thereof and monacolin k | |
WO2013138411A1 (en) | Substances for reducing occurrence of major cardiac events comprising omega-3 polyunsaturated fatty acid or derivatives thereof and high-monacolin k content red yeast rice extract |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PUAL | Search report despatched |
Free format text: ORIGINAL CODE: 0009013 |
|
AK | Designated contracting states |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17P | Request for examination filed |
Effective date: 19911005 |
|
17Q | First examination report despatched |
Effective date: 19920302 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Effective date: 19950524 Ref country code: DK Effective date: 19950524 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 19950524 Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 19950524 Ref country code: AT Effective date: 19950524 |
|
REF | Corresponds to: |
Ref document number: 122884 Country of ref document: AT Date of ref document: 19950615 Kind code of ref document: T |
|
REF | Corresponds to: |
Ref document number: 69019565 Country of ref document: DE Date of ref document: 19950629 |
|
ET | Fr: translation filed | ||
ITF | It: translation for a ep patent filed |
Owner name: STUDIO TORTA SOCIETA' SEMPLICE |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2072387 Country of ref document: ES Kind code of ref document: T3 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19950824 |
|
NLV1 | Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act | ||
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19960331 |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PFA Owner name: SUNTORY LTD Free format text: SUNTORY LTD#NO. 1-40 DOJIMAHAMA 2-CHOME#KITA-KU/OSAKA-SHI/OSAKA (JP) -TRANSFER TO- SUNTORY LTD#NO. 1-40 DOJIMAHAMA 2-CHOME#KITA-KU/OSAKA-SHI/OSAKA (JP) |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: BOVARD AG PATENTANWAELTE Ref country code: CH Ref legal event code: PUE Owner name: SUNTORY HOLDINGS LIMITED Free format text: SUNTORY LTD#NO. 1-40 DOJIMAHAMA 2-CHOME#KITA-KU/OSAKA-SHI/OSAKA (JP) -TRANSFER TO- SUNTORY HOLDINGS LIMITED#1-40, DOJIMAHAMA 2-CHOME KITA-KU OSAKA-SHI#OSAKA (JP) |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20090317 Year of fee payment: 20 Ref country code: GB Payment date: 20090304 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20090401 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20090318 Year of fee payment: 20 Ref country code: DE Payment date: 20090226 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20090316 Year of fee payment: 20 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20100305 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20100308 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100308 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100306 |